Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease with a poor prognosis. Previous research has revealed that the gut microbiota is associated with human health and immunity, and it interacts with the lung through the “gut-lung axis”. This study explores the potential relationship between Gut Microbiome Metabolites and Idiopathic pulmonary fibrosis via Network Pharmacology Study. The metabolites from gut microbiota were retrieved from the gutMGene database, and gene targets for these metabolites were obtained from previous studies. Gene targets of IPF were obtained from public databases (DisGeNET, OMIM). Subsequently, following the identification of shared targets, IL6 was determined as the core target through protein-protein interaction analysis. Then, a microbiota-metabolite-target-signaling pathway network (MMTS) was constructed using Cytoscape 3.10, and targets with low expression in the lungs and intestines were deleted. The MMTS network revealed that three short-chain fatty acids—acetate, butyrate, propionate, and a flavonoid compound called equol—are IL6-related metabolites. Then, we performed a molecular docking test (MDT) using CB-Dock2 to validate the affinity between core targets and metabolites. MDT confirmed that equol produced by the conversion of isoflavones from Lactobacillus paracasei JS1 was more stable in binding to IL6 than the other three short-chain fatty acids, thereby affecting multiple signaling pathways and influencing the progression of IPF. Finally, we validated this hypothesis through in vitro cell culture experiments, further confirming the effect of Equol.
Interstitial lung diseases (ILDs) are a heterogeneous group of chronic lung diseases caused by several potential etiologies but for many, the cause of a given ILD remains unknown. Accurate epidemiologic data are hard to find because of varying definitions, overlapping characteristics once thought to be unique to specific diseases, and ongoing changes in how ILDs are diagnosed and managed. In addition, there are significant variations in prevalence among different geographic populations, likely reflecting a combination of genetic and environmental differences. Certain risk factors, including exposure to cigarette smoke or environmental toxicants (asbestos, silica, fracking, coal dust, and air pollution), genetic mutations, and single nucleotide polymorphisms, have all been associated with developing interstitial lung disease. Due to the availability of high-resolution computed tomography (CT) scans, earlier and broader recognition of subtle imaging changes, and an aging worldwide population, the incidence and prevalence of ILDs are increasing. While a given cause of particular interstitial lung disease may vary, patients often experience breathlessness and a non-productive cough due to impaired alveolar gas exchange. Patients with ILD are prone to the development of acute exacerbations, marked by acute or chronic respiratory failure because of an acute exacerbation of the underlying lung disease. In this review, we discuss the definition of an acute exacerbation and comment on what is known about the underlying pathophysiology in exacerbations of idiopathic pulmonary fibrosis and other ILDs. We also emphasize the similarities in the clinical presentation of the acute exacerbations regardless of the underlying ILD, highlight key prognostic features of the diagnosis, and underscore the importance of interdisciplinary management of acute interstitial lung disease exacerbations.
Fibrosis occurs in many organs, including the lung, heart, skin, liver or kidney, and is characterized by progressive tissue scarring in response to repetitive or chronic non-resolving injury, ultimately leading to organ failure and death. It is, in fact, a major cause of morbidity and mortality worldwide, being estimated to account for 45% of deaths in the world. Despite this fact, little progress has been made therapeutically, and fibrosis remains a major clinical and therapeutic challenge. Although significant advances in our understanding of cellular and molecular mechanisms driving tissue fibrosis have been made, the lack of an efficient treatment reflects the limited insight into the pathophysiological mechanisms underlying the initiation and progression of the fibrotic process. Thus, there is an urgent need for better understanding of tissue fibrosis and repair mechanisms that later lead to the development of new therapeutic approaches to fight fibrosis. The Notch pathway is a highly conserved signaling pathway that has been linked to tissue fibrosis in many organs and promises to open new therapeutic opportunities. This manuscript reviews the relevance of Notch signaling in the development and progression of tissue fibrosis in several organs with a special focus on the Notch3 pathway due to the unique features of this receptor.
The accumulation of extracellular matrix proteins is the hallmark of liver fibrosis associated with all chronic liver disease (CLD) types. Liver fibrosis results from repeated bouts of liver injury, which trigger the wound-healing response, ultimately disrupting the normal hepatic architecture. Over time, fibrosis can progress to cirrhosis, portal hypertension, liver failure, and hepatocellular carcinoma, worsening patient outcomes. Biological modifiers, such as sex and socio-cultural constructs like gender, influence the development of liver fibrosis through various genetic, hormonal, immunological, metabolic, and lifestyle-related factors, including alcohol consumption, diet, sedentary behavior, and hormonal therapy. Moreover, liver fibrosis is significantly modulated by age, reproductive status, and the etiology of CLD. This review aims to summarize the most well-characterized pathomechanisms underlying sex and gender differences in hepatic fibrogenesis as well as liver-related complications (cirrhosis, portal hypertension, hepatic encephalopathy, liver failure, and hepatocellular carcinoma) and extra-hepatic correlates of liver fibrosis (sarcopenia, cardiovascular disease, diabetes, chronic kidney disease, and dementia) across various types of CLD due to viral-related, autoimmune, drug-induced and metabolic etiologies. Understanding these disease modifiers and their mechanisms is crucial for developing innovative treatment strategies and precision medicine approaches in this field.
Fibrosis is defined as the excessive accumulation and disorganized deposition of extracellular matrix components, affecting any organ in the human body. Fibrotic diseases of the vital organs such as lung, heart, kidney and liver can be chronic, progressive, irreversible and fatal. Although fibrotic diseases account for 45% of the mortality in the Western world, the available treatment options are limited in numbers, efficacy and safety. There is certainly a lack of progress in developing novel anti-fibrotics even though the market size for fibrotic diseases is estimated to be ~$30B and several pharmaceutical companies have active R&D programmes in this field. We reviewed the current efforts in developing novel anti-fibrotic medicines focusing on lung, heart, kidney, liver and skin fibrosis. Our analysis revealed an estimated 83% attrition rate from Phase 2 to Phase 3 trials across the five fibrotic diseases. The possible reasons for the slow pace and high attrition rates in developing new anti-fibrotics are discussed and potential solutions are proposed.
Idiopathic pulmonary fibrosis (IPF) is a type of interstitial pneumonia with an unknown cause that progresses gradually, primarily affecting the elderly. The presence of fibrosis has significant implications for individuals with reduced lung compliance, resulting in decreased quality of life and limited survival. Although the exact mechanism remains unclear, researchers have investigated various factors, such as senescent telomerase replication and abnormal lung stem cell differentiation, to understand the root cause. Extensive research has consistently shown that IPF is closely linked to the dysfunction of alveolar epithelial cells. Current scientific studies on IPF cover a range of aspects including oxidative stress, endoplasmic reticulum stress, mitochondrial damage, and iron-induced apoptosis. By examining these mechanisms, a comprehensive model has been developed that explains the process of IPF. Oxidative stress is identified as the primary trigger, followed by mitochondrial damage as a central component, leading to the mesenchymal transformation of alveolar epithelial cells as the ultimate outcome. This model is expected to serve as a valuable reference for understanding the mechanism of IPF and guiding future drug development efforts.
Cellular Communication Network factors 1-6 (CCNs) are matricellular proteins consisting of an N-terminal secretory peptide and four multifunctional structural domains. The CCN1-6 members belonging to this family have a complex network of interacting ligands that can affect diverse signaling pathways through a multitude of mechanisms. Specifically, these proteins play crucial roles in cell proliferation, differentiation, angiogenesis, apoptosis, chondrogenesis, wound repair, and extracellular matrix (ECM) formation/remodeling. This short communication provides a brief summary of the 12th International Workshop on the CCN Family of Genes held at the Scandic Holmenkollen Park Hotel in Oslo, Norway from 20–23 June 2024.
Fibrosis can occur in almost every organ system. It can occur in single organs, such as in idiopathic pulmonary fibrosis (IPF), or affect multiple organs as in systemic sclerosis (SSc). Fibrotic diseases are recognized as major cause of morbidity and mortality in modern societies due to the dysfunction or loss of function of the affected organs. This dysfunction is caused by progressive deposition of extracellular matrix proteins released by activated fibroblasts. Activation of fibroblasts and differentiation into myofibroblasts is required for physiological tissue remodeling, e.g, during wound healing. Disruption of regulatory mechanisms, however, results in chronic and uncontrolled activity of fibroblasts and myofibroblasts. Intensive research during the past years identified several core pathways of pathophysiological relevance, and described different fibroblast subsets based on their expression profile in fibrotic tissue. Herein, we discuss the molecular changes in fibroblasts leading to persistent activation during fibrotic tissue remodeling with a focus on lung fibrosis and SSc.
Fibrosis is defined by scarring and tissue hardening caused by excess deposition of extracellular matrix components, mainly collagens. A fibrotic response can occur in any tissue of the body and is the final outcome of an unbalanced reaction to inflammation and wound healing induced by a variety of insults, including persistent infections, autoimmune reactions, allergic responses, chemical exposure, radiation, and tissue injury. The accumulation of extracellular matrix proteins replaces the living tissue and disrupts the architecture leading to organ malfunction. Fibrosis remains a major clinical and therapeutic challenge and has been estimated to account for 45% of deaths in the developed world. While major advances regarding mechanistic knowledge on the underlying cell biology alterations in fibrosis have helped to characterize the main phases and mediators involved, this knowledge has not yielded significant progress in treatment. Only recently, the metabolic features associated to fibrosis have begun to emerge. This information, likely representing only the tip of the iceberg, suggests that metabolic derangement is a key culprit in the pathophysiology of fibrogenesis. The Workshop on The Cellular and Metabolic Bases of Organ Fibrosis, International University of Andalusia, Baeza, Spain, October 8–11, 2023 aimed to discuss the current knowledge and novel perspectives on the mechanisms contributing to the development of fibrosis in different organs and tissues, with particular focus on new methodological developments in metabolomics and therapeutic strategies.
The endoplasmic reticulum (ER) to Golgi secretory pathway is an elegantly complex process whereby protein cargoes are manufactured, folded, and distributed from the ER to the cisternal layers of the Golgi stack before they are delivered to their final destinations. The export of large bulky cargoes such as procollagen and its trafficking to the Golgi is a sophisticated mechanism requiring TANGO1 (Transport ANd Golgi Organization protein 1. It is also called MIA3 (Melanoma Inhibitory Activity protein 3). TANGO1 has two prominent isoforms, TANGO1-Long and TANGO1-Short, and each isoform has specific functions. On the luminal side, TANGO1-Long has an HSP47 recruitment domain and uses this protein to collect collagen. It can also tether its paralog isoforms cTAGE5 and TALI and along with these proteins enlarges the vesicle to accommodate procollagen. Recent studies show that TANGO1-Long combines retrograde membrane flow with anterograde cargo transport. This complex mechanism is highly activated in fibrosis and promotes the excessive deposition of collagen in the tissues. The therapeutic targeting of TANGO1 may prove successful in the control of fibrotic disorders. This review focuses on TANGO1 and its complex interaction with other procollagen export factors that modulate increased vesicle size to accommodate the export of procollagen.
